Crystal structure of parallel quadruplexes from human telomeric DNA

  title={Crystal structure of parallel quadruplexes from human telomeric DNA},
  author={Gary N Parkinson and Michael P H Lee and Stephen Neidle},
Telomeric ends of chromosomes, which comprise noncoding repeat sequences of guanine-rich DNA, are fundamental in protecting the cell from recombination and degradation. Disruption of telomere maintenance leads to eventual cell death, which can be exploited for therapeutic intervention in cancer. Telomeric DNA sequences can form four-stranded (quadruplex) structures, which may be involved in the structure of telomere ends. Here we describe the crystal structure of a quadruplex formed from four… 
Molecular dynamics and principal components analysis of human telomeric quadruplex multimers.
The addition of a ligand to the model confirms the hypothesis that flat planar chromophores stabilize G-quadruplex structures by making them less flexible and confirms the stability of the central G-tetrads, the individual quadruplexes, and the resulting multimers.
Telomeric quadruplexes as therapeutic targets
Human telomeric quadruplex conformations studied by pulsed EPR.
Investigation of quadruplex conformations under near physiological conditions utilizing double nitroxide modified telomeric sequences in combination with a two frequency pulsed electron paramagnetic resonance (EPR) method (Figure 1 a).
Intramolecular quadruplex conformation of human telomeric DNA assessed with 125I-radioprobing.
It is believed that the two antiparallel and the parallel conformations may coexist in solution, and that their relative proportion is determined by the type and concentration of ions.
A crystallographic and modelling study of a human telomeric RNA (TERRA) quadruplex
The findings suggest that the 2′-OH hydroxyl groups in the RNA quadruplex play a significant role in redefining hydration structure in the grooves and the hydrogen bonding networks, which leads to greater stability through enhanced hydrogen bonded networks.
The structures of quadruplex nucleic acids and their drug complexes.
  • S. Neidle
  • Biology, Chemistry
    Current opinion in structural biology
  • 2009
Human telomeric sequence forms a hybrid-type intramolecular G-quadruplex structure with mixed parallel/antiparallel strands in potassium solution
The folding structure of the human telomeric sequence in K+ solution determined by NMR demonstrates a novel, unprecedented intramolecular G-quadruplex folding topology with hybrid-type mixed parallel/antiparallel G-strands, and suggests a straightforward pathway for the secondary structure formation with effective packing within the extended human telomersic DNA.
Structural basis for binding of porphyrin to human telomeres.
The crystal structure of a bimolecular human telomeric quadruplex, of the sequence d(TAGGGTTAGGG), in a complex with the quadruplex-binding ligand 5,10,15,20-tetrakis(N-methyl-4-pyridyl)porphyrin (TMPyP4) to a resolution of 2.09 A.
Kinetic Partitioning Modulates Human Telomere DNA G-Quadruplex Structural Polymorphism
Rec reconstructed distributions of telomere DNA GQ conformations generated by an in situ refolding protocol commonly employed in single-molecule studies of GQ structure, or using a slow cooling DNA annealing protocol typically used in the preparation of G Q samples for ensemble biophysical analyses suggest the choice of GZ folding protocol has a marked impact on the observed distributions of DNA conformations under otherwise identical buffer conditions.
Structural diversity and specific recognition of four stranded G-quadruplex DNA.
This review is an attempt to summarize the rapidly evolving literature exploring the amazing polymorphism of G-quadruplexes, and understanding their structure-specific-recognition and biological relevance, keeping in mind that G-tetraplexes are not only important drug targets, but may also act as gene regulatory elements.


Quadruplex structure of Oxytricha telomeric DNA oligonucleotides
THE telomeres of most eukaryotes contain a repeating G-rich sequence with the consensus d(T/A)1–4G1–8, of which 12–16 bases form a 3' single-strand overhang beyond the telomeric duplex1. It has been
Solution structure of the human telomeric repeat d[AG3(T2AG3)3] G-tetraplex.
In vitro generated antibodies specific for telomeric guanine-quadruplex DNA react with Stylonychia lemnae macronuclei
Experimental evidence is provided that the telomeres of Stylonychia macronuclei adopt in vivo a guanine-quadruplex structure, indicating that this structure may have an important role for telomere functioning.
Structure and stability of human telomeric sequence.
The overall structure and stability of telomeric sequences are modulated by the cation present, loop sequence, and the number of G tracts, which might be important for the telomere function.
Accelerated assembly of G-quadruplex structures by a small molecule.
Results imply that some biological effects elicited by G- quadruplex-interactive agents, such as the induction of anaphase bridges, may stem from the propensity such compounds have for assembling G-quadruplexes.
The crystal structure of a parallel-stranded guanine tetraplex at 0.95 A resolution.
Evidence that the sugar conformation is strained is presented and it is proposed that this originates from forces that optimize guanine base stacking, which results from a simple crankshaft rotation that requires no net change in theugar conformation.
Normal human chromosomes have long G-rich telomeric overhangs at one end.
It is shown that following replication the daughter telomeres have different terminal overhangs in normal diploid telomerase-negative human fibroblasts, and variations in lagging-strand synthesis may regulate the rate of telomere shortening in normaldiploid human cells.
Structural characterization of a guanine-quadruplex ligand complex.
It was concluded that the externally bound ligand complexes best represent the structure of this quadruplex complex, in agreement with earlier NMR results on related systems.
Inhibition of the Bloom's and Werner's syndrome helicases by G-quadruplex interacting ligands.
It is shown that trisubstituted acridine ligands are potent inhibitors of the helicase activity of the BLM and WRN proteins on both G-quadruplex and B-form DNA substrates.